Mechanisms of resistance to EGFR targeted therapies

Abstract

EGFR is a validated therapeutic target in many human cancers. EGFR targeted therapies are in widespread clinical use in patients with non-small cell lung cancer and other tumor types. Despite the clinical success of EGFR targeted therapy, resistance to treatment is a significant barrier to the optimized use of EGFR inhibitors to cure patients with lung and other cancers. Here, we review established and emerging mechanisms of resistance to EGFR targeted therapy and highlight strategies that could overcome treatment resistance and therefore enhance clinical outcomes.

Keywords: EGFR; EGFR TKI; erlotinib; kinase; lung cancer; resistance; targeted therapy.

Figure 1. A schematic of the molecular pathways implicated in resistance to EGFR TKIs. Mutations in the EGFR kinase domain (predominantly T790M, which accounts for 50–60% of EGFR inhibitor resistance) abrogate the ability of first generation EGFR TKIs to inhibit mutant EGFR. Second generation EGFR TKIs BIBW2992, PF299804 and WZ4002 are currently in clinical trials and show promise as inhibitors of EGFR T790M. EGFR TKI resistance can also occur via upregulation or activation of other RTKs, such as AXL (20–25%), MET (5%) and HER2, which can bypass the inhibition of oncogenic EGFR signaling and activate downstream effector pathways. RTK-independent activation of some of these downstream effectors can also occur, leading to resistance. PTEN loss and activating PI3K mutations (i.e., E545K) have been observed, leading to constitutive AKT activation. Activating BRAF V600E mutations and MAPK1 amplification have been reported which lead to hyper-activation of MAPK signaling and resistance. NFκB pathway activation has been associated with resistance to EGFR TKI treatment. The Epithelial-Mesenchymal Transition (EMT) and transition to small-cell neuroendocrine phenotype have each been associated with resistance to EGFR TKIs, though the mechanistic underpinnings of these observations are unclear.